A long term objective is to understand the pharmacology of cocaine. The pharmacokinetic characteristics and effects of cocaine and some of its major metabolites will be measured in human volunteer research subjects. Higher dose levels will be studied than has hitherto been done in controlled laboratory studies. Bioavailability and other standard pharmacokinetic indices will be measured after intravenous, oral, nasal and buccal routes of administration. Particular attention will be paid to investigation of kinetics and possible biological effects of benzoylecgonine and ecgonine methyl ester. Dose dependent kinetic differences will be explored after both single dose and intravenous infusions under steady state conditions. In vitro experiments will investigate mechanisms accounting for individual differences in metabolism and response. The possible effects of benzoylecgonine, such as they can be separated from the effects of cocaine, will be measured. Gas chromatographic assays of plasma and urine will measure cocaine, benzoylecgonine and ecgonine methyl ester levels. Heart rate, blood pressure, skin temperature, blood catecholamine levels and electroencephalographic evoked potential and spectral analysis measures will assess cocaine and metabolite effects. Subjective symptoms and mood will be measured. Better understanding of cocaine pharmacology and particularly benzoylecgonine and ecgonine methyl ester metabolism has significance for assissing the consequences of cocaine use as well as resolving forensic taxicologic questions. Benzoylecgonine is being used as a marker of cocaine use and ecgonine methyl ester has been suggested as a useful marker, yet little controlled quantitative research, particularly relationships between cocaine dose and the time of last use and metabolite levels, has been done in humans with those metabolites. The proposed studies should provide necessary information for further investigations of cocaine interactions with other drugs; for example, neuroleptics, antidepressants, nicotine, cannabis, oplates, other stimulants and drugs that may help understand cocaine's mechanisms of action.